In recent years, NIDA has encouraged research on vulnerability to substance abuse. A particularly salient issue concerns the specificity of the vulnerability underlying alcohol and other substance abuse disorders. The present proposal will address this issue, focusing on differential drug response as a contributor to differences in vulnerability. The three specific aims of the proposed study are (1) to test the effect of family history of alcoholism on response to a stimulant drug, (2) to test the effect of family history of alcoholism on response to a sedative drug, and (3) to examine the relationship within subjects between stimulant and sedative drug responses. In five testing sessions, differences between family history positive (FHP) (N=30) and family history negative (FHN) (N=30) subjects in psychophysiological response to a stimulant and a sedative drug will be examined. The test battery will consist of the resting electroencephalogram (EEG), the event-related potential (ERP) recorded in an oddball paradigm, the Continuous Performance Test (CPT) of sustained attention, standing stability, and one behavioral and two self-report measures of subjective drug effects. Subjects will receive (in five separate sessions) two doses each of d-amphetamine (5 and 15 mg) and alcohol (0.5 and 1.0 g/kg), and a placebo. The 35-minute test battery will be administered once prior to drug ingestion and three times after ingestion to permit family history effects (Aims 1 and 2) and stimulant-sedative concordance (Aim 3) to be analyzed at various points in time. This study will replicate previous studies of response to acute alcohol challenge in FHP and FHN groups, addressing inconsistencies in the literature, and will extend previous research by testing FHP-FHN differences in response to a stimulant drug. In addition, the proposed study will provide unique data on the concordance of stimulant and sedative drug response in human subjects. As such, the project will address a biological mechanism that may underlie the use and abuse of multiple drugs.